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Autacoids and respiratory system - Pharmacology for Medical Graduates, 4th Updated Edition

Shanbhag, Tara V, MD; Shenoy, Smita, MD;

Pharmacology for Medical Graduates, 4th Updated Edition, CHAPTER 6, 230-262


Autacoids are produced by cells and act locally. Hence, they are also called ‘local hormones’. Various autacoids are histamine, serotonin (5-hydroxytryptamine [5-HT]), prostaglandins (PGs), leukotrienes, angiotensin, kinins and platelet-activating factor (PAF).

Histamine and antihistamines PH1.16

Histamine is a biogenic amine present in many animal and plant tissues. It is also present in venoms and stinging secretions. It is synthesized by decarboxylation of the amino acid, histidine. It is mainly present in storage granules of mast cells in tissues like skin, lungs, liver, gastric mucosa and placenta. It is one of the mediators involved in inflammatory and hypersensitivity reactions.

Mechanism of action and effects of histamine

Histamine exerts its effects by binding to histamine (H) receptors.

Histamine liberators

Many agents release histamine from mast cells ( Fig. 6.1 ).

Fig. 6.1
Histamine liberators and its effects.

Uses

Histamine has no valid clinical use.

Betahistine

It is a histamine analogue that is used orally to treat vertigo in Meniere’s disease. It probably acts by improving blood flow in the inner ear. The side effects are nausea, vomiting, headache and pruritus. It should be avoided in patients with asthma and peptic ulcer.

H 1 -receptor antagonists (H 1 -blockers, antihistamines) PH1.16

Classification

Mechanism of action of H 1 -blockers

H 1 -antihistamines antagonize the effects of histamine by competitively blocking the H 1 -receptors (competitive antagonism).

First-generation H 1 -blockers

They are conventional antihistamines.

Pharmacological actions

  • 1.

    H 1 -blockers cause CNS depression, sedation and drowsiness. Certain antihistamines have antiemetic, local anaesthetic and anti-parkinsonian effects.

  • 2.

    They have antiallergic action; hence, most of the manifestations of type I reactions are suppressed.

  • 3.

    They have anticholinergic actions – cause dryness of mouth, blurring of vision, constipation, urinary retention.

Pharmacokinetics

H 1 -antihistamines are well absorbed after oral and parenteral administration. They are distributed widely throughout the body, metabolized extensively in liver and excreted in urine.

Adverse effects

  • 1.

    The common adverse effects are sedation, drowsiness, lack of concentration, headache, fatigue, weakness, lassitude, psychomotor incoordination, etc. Hence, H 1 -antihistamines should be avoided while driving or operating machinery. These adverse effects are rare with second-generation antihistamines.

  • 2.

    Gastrointestinal side effects are nausea, vomiting, loss of appetite and epigastric discomfort.

  • 3.

    Anticholinergic side effects such as dryness of mouth, blurring of vision, constipation and urinary retention. These effects are not seen with second-generation antihistamines.

  • 4.

    Teratogenic effects of some H 1 -blockers have been observed in animals.

  • 5.

    Allergic reactions may occur rarely with these agents, especially contact dermatitis on topical application.

Uses

  • 1.

    Allergic diseases: H 1 -antihistamines are used to prevent and treat symptoms of allergic reactions. For example, pruritus, urticaria, dermatitis, rhinitis, conjunctivitis and angioedema of lips respond to these drugs.

  • 2.

    Common cold: They produce symptomatic relief by sedative and anticholinergic actions.

  • 3.

    Preanaesthetic medication: Promethazine is used for its sedative and anticholinergic effects.

  • 4.

    As antiemetic: Promethazine, diphenhydramine, dimenhydrinate, etc. are useful for prophylaxis of motion sickness because of their anticholinergic action. They act probably on the vestibular apparatus or cortex. Sedative effect also contributes to their beneficial effect. These drugs are useful in drug-induced and postoperative vomiting. Promethazine, in combination with other antiemetics, is used to control vomiting due to cancer chemotherapy and radiation therapy.

  • 5.

    Parkinsonism: Imbalance between dopamine (DA) and acetylcholine (↓DA or ↑ACh) in the basal ganglia produces parkinsonism. Promethazine, diphenhydramine or orphenadrine are used to control tremor, rigidity (central action) and sialorrhoea of parkinsonism due to their anticholinergic and sedative properties. Promethazine and diphenhydramine are useful for the treatment of idiopathic and drug-induced parkinsonism.

  • 6.

    H 1 -blockers are used to control mild blood transfusion and saline infusion reactions (chills and rigors) and as adjunct in anaphylaxis.

  • 7.

    Cinnarizine, dimenhydrinate and meclizine are effective for controlling vertigo in Meniere’s disease and other types of vertigo. Their antihistaminic and anticholinergic actions are useful in this condition.

  • 8.

    Sedative and hypnotic: H 1 -antihistamines (e.g. promethazine and diphenhydramine) are used to induce sleep, especially in children during minor surgical procedures.

Second-generation H 1 -blockers ( table 6.1 )

Cetirizine, levocetirizine, loratadine, desloratadine, azelastine, fexofenadine, etc. are highly selective for H 1 -receptors and have the following properties. They:

  • 1.

    Have no anticholinergic effects.

  • 2.

    Lack antiemetic effect.

  • 3.

    Do not cross blood–brain barrier (BBB), hence cause minimal/no drowsiness.

  • 4.

    Do not impair psychomotor performance.

  • 5.

    Are relatively expensive.

Table 6.1 ■
Second-generation H 1 -blockers
Drug Route and duration of action Important features
Cetirizine p.o., 12–24 hours
  • H 1 -blocker; inhibits histamine release; achieves good concentration in the skin; poorly crosses BBB; may cause drowsiness

  • Drug interactions rare

Levocetirizine p.o., 12–24 hours More potent and produces less adverse effects than cetirizine
Loratadine
Desloratadine
Mizolastine
Ebastine
p.o., 24 hours
  • Long acting, nonsedating agents

  • Cardiac arrhythmias have been noticed in animals treated with ebastine

  • No cardiac arrhythmias with loratadine and desloratadine

  • Loratadine may rarely cause seizures

Fexofenadine p.o., 12–24 hours
  • Active metabolite of terfenadine

  • Nonsedating agent

  • Arrhythmias rare; avoid in patients with prolonged QT interval

Azelastine Topical (nasal spray, eye drops), 12–24 hours
  • H 1 -blocker; inhibits histamine release

  • Produces active metabolite

  • Has a rapid onset and long duration of action

  • Taste alteration, burning sensation in the nose, drowsiness

Rupatadine p.o. H 1 -blocker + blocks actions of platelet-activating factor

Cetirizine is one of the commonly used second-generation antihistamines. In addition to H 1 -blocking effect, it can also inhibit the release of histamine. It causes minimal/or no drowsiness. It is not metabolized in the body. Incidence of cardiac arrhythmias is rare with this drug.

Uses

Second-generation H 1 -blockers are used in various allergic disorders, e.g. rhinitis, dermatitis, conjunctivitis, urticaria, eczema, drug and food allergies. For allergic rhinitis or hay fever, fexofenadine, cetirizine, mizolastine or rupatadine are used orally. Azelastine is used as nasal spray in allergic rhinitis. For urticaria, atopic dermatitis and other skin allergies, fexofenadine, cetirizine, mizolastine, loratadine and ebastine are useful. Azelastine and levocabastine are available as eye drops for allergic conjunctivitis.

Antivertigo drugs

Vertigo is a sensation of rotation or movement of one’s self or of one’s surrounding in any plane. Antivertigo drugs are cinnarizine, promethazine and diphenhydramine (H 1 -blockers), hyoscine (anticholinergic), prochlorperazine (phenothiazine), betahistine (H 1 -analogue), acetazolamide, thiazides and furosemide (diuretics), diazepam (benzodiazepine), amitriptyline (tricyclic antidepressant [TCA]), glucocorticoids, etc. Cinnarizine is a first-generation H 1 -blocker. It decreases entry of calcium into vestibular cells and relieves vertigo. Antihistaminics, anticholinergics and prochlorperazine act as labyrinthine suppressants. Corticosteroids decrease oedema in the labyrinth.

5-hydroxytryptamine: Agonists and antagonists PH1.16

5-HT (serotonin) is an important neurotransmitter, widely distributed in plants and animals. It is synthesized from an amino acid, tryptophan. High concentration of 5-HT is found in the intestine, platelets and brain. 5-HT is involved in several conditions such as migraine, affective disorders, psychoses, GI disorders and sleep. There are seven subtypes of serotonin receptors (1–7). All of them are G-protein–coupled receptors, except 5-HT 3 (ligand-gated ion channel). The serotonin receptor subtypes are shown in Table 6.2 .

Table 6.2 ■
Serotonin receptor subtypes
Receptor Location Important actions Drugs
5-HT 1 CNS, cranial blood vessels
  • Autoreceptors: Decrease 5-HT release from nerve endings

  • Constriction of cranial blood vessels

  • Decreased release of peptides from nerve endings

  • Buspirone (5-HT 1A partial agonist)

  • Triptans (Selective 5-HT 1B/1D agonists)

  • Ergotamine (antagonist/partial agonist at all subtypes of 5-HT 1 receptors)

5-HT 2
  • Platelets

  • Smooth muscles

  • Cerebral cortex (5-HT 2A )

  • Fundus of the stomach (5-HT 2B )

  • Choroid (5-HT 2C )

  • Platelet aggregation

  • Contraction of smooth muscles

  • Activation of neurons

  • Contraction

  • CSF production

  • Ketanserin (5-HT 2A antagonist)

  • Cyproheptadine (5-HT 2A antagonist)

  • Methysergide (5-HT 2A/2C antagonist)

  • Atypical antipsychotics (5-HT 2A antagonists)

5-HT 3 CTZ, NTS, parasympathetic nerve terminals (GIT)
  • Vomiting

  • Peristalsis

Ondansetron, granisetron (5-HT 3 antagonists)
5-HT 4 GIT, CNS Peristalsis Metoclopramide, prucalopride (5-HT 4 agonists)
5-HT 5–7 CNS

5-HT antagonists

Cyproheptadine

  • H 1 -receptor and 5-HT 2A blocker

  • Has sedative, antipruritic and anticholinergic effects

  • Increases appetite

  • Useful in carcinoid and postgastrectomy dumping syndrome (to control GI manifestations)

  • Dry mouth, drowsiness, weight gain are some of the side effects

Ketanserin

  • 5-HT 2A antagonist and α 1 -blocker

  • Has antihypertensive effect

Ondansetron and granisetron

They are 5-HT 3 receptor antagonists used as antiemetics.

Atypical antipsychotics

Clozapine, olanzapine, quetiapine, risperidone, etc. are 5-HT 2 blockers used in schizophrenia.

Methysergide

  • 5-HT 2A/2C antagonist.

  • It was used for prophylaxis of migraine.

  • Long-term use causes abdominal and pulmonary fibrosis.

Ergot alkaloids

Ergot alkaloids occur naturally in a fungus, Claviceps purpurea . The most important compounds and their therapeutic uses are given in Table 6.3 .

Table 6.3 ■
Ergot alkaloids and their derivatives
Drug Action on receptor Effects Use with route Adverse effects
Ergotamine (natural alkaloid) Partial agonist/antagonist at α, 5-HT 1 and 5-HT 2 receptors Contraction of smooth muscles – blood vessels, uterus, gut and other viscera Acute migraine (oral, sublingual, rectal) Vomiting, diarrhoea; overdosage – severe vasospasm → gangrene
Dihydroergotamine (semisynthetic)
  • Predominant α-blockade

  • Weak 5-HT and α-agonistic action

  • Smooth muscle contraction less than ergotamine

  • Less vasoconstrictor effect (safer than ergotamine for parenteral use)

Acute migraine (oral, i.m., s.c.) Nausea, vomiting
Ergometrine (ergonovine; natural alkaloid)
  • Partial agonist at 5-HT 2 and weak action at α-receptors

  • No α-antagonistic action

  • Major action – contraction of myometrium

  • Vasoconstriction is minimal

Postpartum haemorrhage (i.m., i.v.) Nausea, vomiting, rise in BP
Bromocriptine (semisynthetic) D 2 -agonist Decreases prolactin release
  • Parkinsonism

  • Galactorrhoea (oral)

Vomiting, hypotension

Ergot alkaloids are contraindicated in ischaemic heart disease, hypertension, peripheral vascular disease and renal disease.

Drug therapy of migraine PH1.16

Migraine is a common and debilitating condition, the cause of which is not clear. A migraine attack consists of an initial visual disturbance (the aura), severe throbbing headache often with photophobia, nausea and vomiting.

Drugs for acute attack of migraine

Nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used alone or in combination. They provide symptomatic relief but should not be taken on a long-term basis, e.g. paracetamol, aspirin, ibuprofen, naproxen, diclofenac and mefenamic acid. They are useful in mild and moderate migraine.

Antiemetics (oral or parenteral).

They are used to treat nausea and vomiting associated with the attack. They also improve absorption of oral medications used to treat migraine, e.g. metoclopramide, domperidone, prochlorperazine, promethazine and diphenhydramine.

Ergot preparations

Ergotamine.

Oral/sublingual/suppository preparation is used at the onset of pain or warning symptoms. It is used in moderate to severe migraine.

Mechanism of action.

It acts as a partial agonist at 5-HT 1B/1D receptors in cranial blood vessels → constriction of dilated cranial blood vessels, decreases inflammation and extravasation of plasma into perivascular space.

Ergotamine is available in combination with caffeine. Caffeine increases absorption of ergotamine. It also has vasoconstrictor effect on cranial blood vessels like ergotamine.

Dihydroergotamine.

It is administered parenterally (i.m., i.v., s.c.) at the time of attack. It is safer for parenteral use than ergotamine.

Triptans.

Selective 5-HT 1B/1D agonists, include sumatriptan, rizatriptan, eletriptan, almotriptan, zolmitriptan, naratriptan, frovatriptan, etc. They are used in moderate and severe migraine.

Mechanism of action of triptans (selective 5-HT 1B/1D agonists)

By inhibiting the release of inflammatory peptides from the nerve endings in the perivascular space, they decrease inflammation. They are the preferred drugs for acute attack of migraine. All triptans are administered orally. Sumatriptan can also be administered by s.c. and nasal routes; zolmitriptan can also be given by nasal route. Sumatriptan is rapid acting and has a half-life of 2 hours. Other triptans have a higher oral bioavailability than sumatriptan. Frovatriptan and naratriptan have longer half-life than sumatriptan.

Adverse effects and contraindications of triptans.

They include paraesthesia, tightness in the chest, flushing and dizziness. Nausea may occur. Pain at the site of injection is common. They may cause a rise in BP and coronary vasospasm. Triptans are contraindicated in pregnancy, patients with ischaemic heart disease, and those with peripheral vascular disease, hypertension and risk factor for coronary artery disease. Triptan and ergot preparations should not be coadministered; neither should triptans be taken within 24 hours of an ergot derivative.

Prophylaxis of migraine (note ABCD)

Prophylactic treatment may be required if migraine headaches occur two/three or more times in a month or if there is significant functional impairment during the attack. The drugs used are as follows:

  • 1.

    B eta-blockers: Propranolol, timolol, atenolol, metoprolol, etc. Propranolol is more effective than other β-blockers; requires prolonged treatment. The mechanism of action is unknown.

  • 2.

    Anti d epressants: TCAs like amitriptyline help to reduce attacks of migraine; exact mechanism of action of antimigraine effect is not clear. TCAs produce undesirable side effects on prolonged therapy.

  • 3.

    C alcium channel blockers (CCBs): For example, verapamil and flunarizine. They reduce the frequency of attacks. Flunarizine is selective for cerebral calcium channels; it also has Na + channel–blocking effect. CCBs should not be co-administered with β-blockers.

  • 4.

    A nticonvulsants: For example, gabapentin, sodium valproate and topiramate are used for migraine prophylaxis.

Others: Methysergide and cyproheptadine are rarely used for prophylaxis of migraine.

Prostaglandins and leukotrienes (eicosanoids) PH1.16

Prostaglandins

PGs are the products of long-chain fatty acids. Arachidonic acid is the precursor for biosynthesis of all PGs. The enzyme involved in the formation of PGs from arachidonic acid is cyclooxygenase (COX). The main PGs are PGE 2 , PGF and PGI 2 . Another class of substances obtained from arachidonic acid by the action of lipoxygenase is leukotrienes.

There are two forms of COX, called COX-1 and COX-2 ( Fig. 6.2 ). COX-1 is constitutive (it is always present) and is widely distributed. It participates in various physiological functions such as protection of gastric mucosa, homeostasis and regulation of cell division. COX-2 is induced during inflammation by cytokines and endotoxins.

Fig. 6.2
The different roles of cyclooxygenases (COX-I and COX-2) and the drugs inhibiting them. BV, blood vessels; IOP, intraocular pressure.

Pharmacological actions and uses ( fig. 6.3 )

  • 1.

    GI tract: PGE 2 and PGI 2 reduce acid secretion and increase the secretion of mucus in the stomach (cytoprotective action). Misoprostol (PGE 1 analogue) is used for the prevention of NSAID-induced ulcers ( Table 6.4 ).

    Fig. 6.3
    Effects and uses of prostaglandins. Note: PGs – in the figure, actions/uses with plenty of ‘ P ’s and a single ‘ G ’.
    Table 6.4 ■
    Preparations, formulations and uses of prostaglandin analogues
    Preparations Formulations/route Uses
    • Dinoprostone (PGE 2 )

    • Vaginal tab

    • Vaginal gel

    • Induction of labour

    • Mid-term abortion

    • Termination of pregnancy

    • Dinoprost (PGF )

    Intra-amniotic injection Mid-term abortion
    • Carboprost (15-methyl PGF )

    i.m.
    • Mid-term abortion

    • Control of PPH

    • Gemeprost (PGE 1 )

    Vaginal pessary Cervical priming in early pregnancy
    • Alprostadil (PGE 1 )

    • Intravenous infusion

    • Intracavernous injection

    • To maintain the patency of ductus arteriosus in neonates with congenital heart disease until surgery

    • Erectile dysfunction

    • Misoprostol (PGE 1 )

    Oral, vaginal pessary
    • Peptic ulcer

    • Abortion, PPH

    • Epoprostenol (PGI 2 )

    • Treprostinil (PGI 2 )

    • Iloprost (PGI 2 )

    Intravenous infusion Pulmonary hypertension
    • Latanoprost (PGF )

    • Bimatoprost (PGF )

    • Unoprostone (PGF )

    • Travoprost (PGF )

    Topical (eye drops) Glaucoma

  • 2.

    Cardiovascular system: PGD 2 , PGE 2 and PGI 2 cause vasodilatation. PGF constricts pulmonary veins and arteries. TXA 2 is a vasoconstrictor.

    • (a)

      PGE 1 (alprostadil) is used to maintain the patency of ductus arteriosus before surgery.

    • (b)

      Prostacyclin (PGI 2 ) decreases peripheral, pulmonary and coronary resistance. PGI 2 (epoprostenol) is used to treat pulmonary hypertension. Other PGI 2 analogues useful in this condition are treprostinil and iloprost.

  • 3.

    Platelets: PGI 2 inhibits platelet aggregation. Hence, it is useful during haemodialysis to prevent platelet aggregation.

  • 4.

    Eye: PGF has been found to decrease intraocular tension. Its analogues, e.g. latanoprost, bimatoprost, travoprost and unoprostone, are used in glaucoma.

  • 5.

    Uterus:

    • (a)

      PGE 2 (low concentration) and PGF contract pregnant uterus; PGs are mainly used in mid-trimester abortion, missed abortion and in hydatidiform mole ( Table 6.4 ).

    • (b)

      Induction of labour: PGE 2 and PGF can induce labour at term.

    • (c)

      Cervical priming: PGE 2, PGE 1 and PGF promote ripening of the cervix; make the cervix favourable for induction and facilitation of labour.

    • (d)

      Postpartum haemorrhage (PPH): PGs increase tone as well as amplitude of uterine contractions. Carboprost (15-methyl PGF ) can be used to control PPH.

  • 6.

    Male reproductive system: PGE 1 (alprostadil) is useful in the treatment of erectile dysfunction.

Therapeutic uses of prostaglandins in obstetrics

  • 1.

    Abortion: PGs stimulate uterine contractions and cause ripening of the cervix.

    • Dinoprostone (vaginal) is used for induction of mid-trimester abortion, missed abortion and hydatidiform mole.

    • Misoprostol (oral or vaginal) can be used in combination with mifepristone or methotrexate to induce abortion in early pregnancy.

    • Carboprost (i.m.) is used to induce abortion in second trimester of pregnancy.

    • Gemeprost (PGE 1 ) and dinoprost (PGF ) are also useful for inducing abortion.

  • 2.

    Induction of labour: PGs can be used to soften the cervix for induction of labour. PGE 2 can facilitate labour by softening and dilatation of cervix.

  • 3.

    PPH: Carboprost (i.m.) and misoprostol (oral) can be used to control PPH.

Adverse effects

They are nausea, vomiting, diarrhoea, fever, flushing, hypotension and backache due to uterine contractions. Injections are painful due to sensitization of nerve endings.

Leukotrienes

These are obtained from arachidonic acid by the action of lipoxygenase.

Leukotriene antagonists

(see p. 259)

Nonsteroidal anti-inflammatory drugs PH1.16

Classification

  • 1.

    Nonselective COX inhibitors

    • (a)

      Salicylates : Aspirin, diflunisal.

    • (b)

      Propionic acid derivatives : Ibuprofen, naproxen, ketoprofen, flurbiprofen.

    • (c)

      Fenamic acid derivatives : Mefenamic acid, flufenamic acid.

    • (d)

      Acetic acid derivatives : Ketorolac, indomethacin.

    • (e)

      Enolic acid derivatives : Piroxicam, tenoxicam, lornoxicam.

  • 2.

    Preferential COX-2 inhibitors: Diclofenac, aceclofenac, nimesulide, meloxicam.

  • 3.

    Highly selective COX-2 inhibitors: Etoricoxib, parecoxib.

  • 4.

    Analgesic and antipyretics having weak anti-inflammatory effect: Paracetamol, nefopam.

Mechanism of action

COX is the enzyme responsible for biosynthesis of various PGs. There are two well-recognized isoforms of COX: COX-1 and COX-2. COX-1 is constitutive, found in most tissues such as blood vessels, stomach and kidney. PGs have important physiological role in many tissues ( Fig. 6.2 ). COX-2 is induced during inflammation by cytokines and endotoxins and is responsible for the production of prostanoid mediators of inflammation.

Aspirin and most of the NSAIDs inhibit both COX-1 and COX-2 isoforms; thereby decrease PGs and thromboxane synthesis. The anti-inflammatory effect of NSAIDs is mainly due to inhibition of COX-2. Aspirin causes irreversible inhibition of COX activity. Rest of the NSAIDs causes reversible inhibition of the enzyme.

Pharmacological actions of aspirin and other nsaids

Aspirin (acetylsalicylic acid) is the prototype drug. The other nonselective NSAIDs vary mainly in their potency, analgesic, anti-inflammatory effects and duration of action.

  • 1.

    Analgesic effect: NSAIDs are mainly used for relieving musculoskeletal pain, dysmenorrhoea and pain associated with inflammation or tissue damage. Analgesic effect is mainly due to peripheral inhibition of PG production. They prevent sensitization of peripheral nerve endings by inflammatory mediators. They also increase pain threshold by acting at subcortical site. These drugs relieve pain without causing sedation, respiratory depression, tolerance or dependence. They are less efficacious than opioids as analgesics. Aspirin produces analgesia at doses of 2–3 g/day.

  • 2.

    Antipyretic effect: The thermoregulatory centre is situated in the hypothalamus. Fever occurs when there is a disturbance in hypothalamic thermostat. NSAIDs reset the hypothalamic thermostat and reduce the elevated body temperature during fever. They promote heat loss by causing cutaneous vasodilatation and sweating. They do not affect normal body temperature. The antipyretic effect is mainly due to inhibition of PGs in the hypothalamus. The dose of aspirin for antipyretic effect is 2–3 g/day.

  • 3.

    Anti-inflammatory effect: Anti-inflammatory effect is seen at high doses (aspirin: 4–6 g/day in divided doses). These drugs produce only symptomatic relief. They suppress signs and symptoms of inflammation such as pain, tenderness, swelling, vasodilatation and leukocyte infiltration but they do not affect the progression of underlying disease.

    • The anti-inflammatory action of NSAIDs is mainly due to inhibition of PG synthesis at the site of injury. They also affect other mediators of inflammation (bradykinin, histamine, serotonin, etc.), thus inhibit granulocyte adherence to the damaged vasculature. NSAIDs also cause modulation of T-cell function, stabilization of lysosomal membrane and inhibition of chemotaxis.

  • 4.

    Antiplatelet (antithrombotic) effect: Aspirin in low doses (50–325 mg/day) irreversibly inhibits platelet TXA 2 synthesis and produces antiplatelet effect, which lasts for 8–10 days, i.e. the life time of the platelets. Aspirin in high doses (2–3 g/day) inhibits both PGI 2 and TXA 2 synthesis, hence antiplatelet effect is lost. Aspirin should be withdrawn 1 week prior to elective surgery because of the risk of bleeding.

  • 5.

    Acid–base and electrolyte balance: In therapeutic doses, salicylates cause respiratory alkalosis, which is compensated by excretion of bicarbonate (compensated respiratory alkalosis). In toxic doses, the respiratory centre is depressed and can lead to respiratory acidosis. Later, there is uncompensated metabolic acidosis.

  • 6.

    GIT: Aspirin irritates the gastric mucosa and produces nausea, vomiting and dyspepsia. The salicylic acid formed from aspirin also contributes to these effects. Aspirin also stimulates CTZ and produces vomiting ( Fig. 6.4 ).

    Fig. 6.4
    Action of aspirin on stomach and CTZ. ⊕, Stimulation; ⊖, inhibition; PGs, prostaglandins.

  • 7.

    CVS: Prolonged use of aspirin and other NSAIDs causes sodium and water retention. They may precipitate CCF in patients with low cardiac reserve. They may also decrease the effect of antihypertensive drugs.

  • 8.

    Urate excretion: Salicylates, in therapeutic doses, inhibit urate secretion into the renal tubules and increase the plasma urate levels. In high doses, salicylates inhibit the reabsorption of uric acid in the renal tubules and produce uricosuric effect.

Pharmacokinetics

Salicylates are rapidly absorbed from the upper GI tract. They are highly bound to plasma proteins but the binding is saturable. Salicylates are well distributed throughout the tissues and body fluids; metabolized in liver by glycine and glucuronide conjugation. In low doses, elimination follows first-order kinetics and with high doses as the metabolizing enzymes get saturated, it switches over to zero-order kinetics. After this, an increase in salicylate dosage increases its plasma concentration markedly and severe toxicity can occur. Alkalinization of urine increases the rate of excretion of salicylates.

Dosage regimen for aspirin

Analgesic dose: 2–3 g/day in divided doses after food.

Anti-inflammatory dose: 4–6 g/day in divided doses after food.

Antiplatelet dose: 50–325 mg/day (low-dose aspirin).

Adverse effects

  • 1.

    GIT: Nausea, vomiting, dyspepsia, epigastric pain, acute gastritis, ulceration and GI bleeding. Ulcerogenic effect is the major drawback of NSAIDs, which is prevented/minimized by taking:

    • (a)

      NSAIDs after food.

    • (b)

      Buffered aspirin (preparation of aspirin with antacid).

    • (c)

      Proton-pump inhibitors/H 2 -blockers/misoprostol with NSAIDs.

    • (d)

      Selective COX-2 inhibitors.

  • 2.

    Hypersensitivity: It is relatively more common with aspirin. The manifestations are skin rashes, urticaria, rhinitis, bronchospasm, angioneurotic oedema and rarely anaphylactoid reaction.

    • Bronchospasm (aspirin-induced asthma) is due to increased production of leukotrienes. Incidence of hypersensitivity is high in patients with asthma, nasal polyps, recurrent rhinitis or urticaria. Therefore, aspirin should be avoided in such patients.

  • 3.

    In people with G6PD deficiency, administration of salicylates may cause haemolytic anaemia.

  • 4.

    Prolonged use of salicylates interfere with action of vitamin K in the liver → decreased synthesis of clotting factors (hypoprothrombinaemia) → predisposes to bleeding (can be treated by administration of vitamin K).

  • 5.

    Reye’s syndrome: Use of salicylates in children with viral infection may cause hepatic damage with fatty infiltration and encephalopathy – Reye’s syndrome. Hence, salicylates are contraindicated in children with viral infection.

  • 6.

    Pregnancy: These drugs inhibit PG synthesis, thereby delay onset of labour and increase chances of PPH. In the newborn, inhibition of PG synthesis results in premature closure of ductus arteriosus.

  • 7.

    Analgesic nephropathy: Slowly progressive renal failure may occur on chronic use of high doses of NSAIDs. Renal failure is usually reversible on stoppage of therapy but rarely NSAIDs may cause irreversible renal damage.

Salicylism

Salicylate intoxication may be mild or severe. The mild form is called salicylism. The symptoms include headache, tinnitus, vertigo, confusion, nausea, vomiting, diarrhoea, sweating, hyperpnoea, electrolyte imbalance, etc. These symptoms are reversible on stoppage of therapy.

Acute salicylate poisoning

It is common in children. Manifestations are vomiting, dehydration, acid–base and electrolyte imbalances, hyperpnoea, restlessness, confusion, coma, convulsions, cardiovascular collapse, pulmonary oedema, hyperpyrexia and death.

Treatment.

There is no specific antidote for salicylate poisoning. Treatment is symptomatic.

  • 1.

    Hospitalization.

  • 2.

    Gastric lavage followed by administration of activated charcoal (activated charcoal adsorbs the toxic material – physical antagonism ).

  • 3.

    Maintain fluid and electrolyte balance. Correct acid–base disturbances.

  • 4.

    Intravenous sodium bicarbonate to treat metabolic acidosis. It also alkalinizes the urine and enhances renal excretion of salicylates (since salicylates exist in ionized form in alkaline pH).

  • 5.

    External cooling.

  • 6.

    Haemodialysis in severe cases.

  • 7.

    Vitamin K 1 and blood transfusion if there is bleeding.

Drug interactions

  • 1.

    NSAIDs × glucocorticoids: Potentiation of GI complications – nausea, vomiting, dyspepsia, epigastric pain, acute gastritis, ulceration and GI bleeding.

  • 2.

    NSAIDs potentiate the effects of oral anticoagulants, oral hypoglycaemic agents (sulphonylureas) and methotrexate by displacing them from plasma protein binding sites.

  • 3.

    Some of the NSAIDs (e.g. piroxicam) can impair the clearance of lithium leading to its toxicity.

  • 4.

    NSAIDs × thiazides/furosemide: NSAIDs by inhibiting PG synthesis promote Na + and water retention on chronic use. Thus, they decrease the diuretic efficacy of thiazides/furosemide.

  • 5.

    NSAIDs × antihypertensives: NSAIDs by inhibiting PG synthesis promote Na + and water retention on chronic use. Thus, they decrease the efficacy of antihypertensives.

Clinical uses of NSAIDs (for basis and explanation, see ‘pharmacological actions’)

  • 1.

    As analgesic: In painful conditions like headache, toothache, backache, body ache, muscle pain, joint pain, bursitis, neuralgias and dysmenorrhoea.

  • 2.

    As antipyretic: To reduce elevated body temperature in fever, paracetamol is preferred because:

    • (a)

      Gastrointestinal symptoms are rare.

    • (b)

      It does not cause Reye syndrome in children.

  • 3.

    Osteoarthritis: In mild cases, paracetamol is used. In severe cases of osteoarthritis, other NSAIDs are more effective than paracetamol. Topical agents like methyl salicylate, diclofenac gel and capsaicin cream can also be used.

  • 4.

    Rheumatoid arthritis (RA): NSAIDs have anti-inflammatory effects and can produce only symptomatic relief but they do not alter the progression of disease.

  • 5.

    Acute rheumatic fever: Aspirin is the preferred drug. It reduces fever, relieves swelling and joint pain, but does not affect the normal course of the disease.

  • 6.

    Thromboembolic disorders: The antiplatelet effect of low-dose aspirin is made use of in the prophylactic treatment of various thromboembolic disorders, such as

    • (a)

      Transient ischaemic attacks

    • (b)

      Myocardial infarction (MI)

      • (i)

        To reduce incidence of recurrent MI

      • (ii)

        To decrease mortality in post-MI patients

  • 7.

    Other uses:

    • (a)

      Medical closure of patent ductus arteriosus (indomethacin is preferred).

    • (b)

      Colon and rectal cancer: Regular use of aspirin is reported to reduce the risk of cancer.

    • (c)

      Aspirin is reported to reduce the risk and retard the onset of Alzheimer’s disease.

    • (d)

      To control radiation-induced diarrhoea.

    • (e)

      To control pruritus and flushing associated with the use of nicotinic acid.

    • (f)

      Low dose of aspirin may be useful in preeclampsia.

Aspirin per se is rarely used at present because of the following disadvantages:

  • 1.

    It has a short duration of action, requires large doses and frequent administration.

  • 2.

    Gastric irritation and ulcerogenic effect are the main drawbacks of NSAIDs. The incidence is high with aspirin.

  • 3.

    Salicylates should be avoided in children with viral infection.

  • 4.

    NSAIDs may precipitate bronchospasm in patients with bronchial asthma (aspirin-induced asthma).

Other NSAIDs ( table 6.5 )

They have similar mechanism of action, pharmacological actions, therapeutic uses and adverse effects. They vary mainly in their potency, duration of action, analgesic and anti-inflammatory effects.

  • Nimesulide

    • Preferential COX-2 inhibitor

    • Has analgesic, antipyretic and anti-inflammatory effects

    • Used in dysmenorrhoea, osteoarthritis, skin, soft tissue and bone inflammatory conditions, etc.

    • Adverse effects: GI irritation is less than aspirin and other NSAIDs; skin rashes, itching, hepatotoxicity has been reported – hence is banned for paediatric use in India

  • Meloxicam

    • Preferential COX-2 inhibitor

    • Has analgesic, antipyretic and anti-inflammatory effects

    • Is long acting

Table 6.5 ■
​Nonsteroidal anti-inflammatory drugs and their important features
Drug Route and formulations with oral dose Other points
  • 1.

    Ibuprofen

Oral and topical gel
Dose: 400–600 mg t.d.s.
  • It has moderate anti-inflammatory effect

  • It is better tolerated than aspirin

  • It can be used in children

  • 2.

    Diclofenac

Oral, i.m., rectal, topical gel and ophthalmic preparation (eye drops)
Dose: 50 mg b.d. or 100 mg sustained release preparation o.d.
  • It has potent anti-inflammatory effect

  • It gets concentrated in synovial fluid, hence preferred in inflammatory conditions (arthritis) of joint

  • Incidence of hepatotoxicity is more

  • Combination of diclofenac with misoprostol (PGE 1 analogue) is available, which reduces GI irritation and peptic ulcer

  • 3.

    Aceclofenac

Oral
Dose: 100 mg b.d. or 200 o.d.
Same as diclofenac
  • 4.

    Indomethacin

    • Note: It has

      • Extra mechanism of action

      • Extra uses

      • Extra side effects

Oral, eye drops and suppository
Dose: 50 mg t.d.s.
  • It is a nonselective COX inhibitor

  • It has potent anti-inflammatory effect

  • It inhibits migration of neutrophils to inflamed area

  • It is very effective in ankylosing spondylitis, acute gout and psoriatic arthritis

  • It has prominent GI side effects

  • CNS side effects are severe headache, confusion, hallucinations, etc.

  • It is contraindicated in epileptics, psychiatric patients and drivers

  • 5.

    Piroxicam

Oral, i.m. and topical gel
Dose: 20 mg o.d.
  • It has potent anti-inflammatory effect

  • It is long acting

  • Increased incidence of peptic ulcer and bleeding

  • 6.

    Ketorolac

Oral, i.m., i.v., ophthalmic preparation and transdermal patch
Dose: 10–20 mg q.i.d.
  • It has potent analgesic effect and efficacy is almost equal to morphine

  • It relieves pain without causing respiratory depression, hypotension and drug dependence

  • It is used in renal colic, postoperative and metastatic cancer pain

  • 7.

    Mefenamic acid

Oral
Dose: 250–500 mg t.i.d.
  • It has analgesic, antipyretic and weak anti-inflammatory effect

  • It is used in dysmenorrhoea, osteoarthritis, rheumatoid arthritis

  • 8.

    Naproxen

Oral
500 mg b.d.
  • Potent anti-inflammatory action

  • Inhibits migration of leukocytes

  • Long acting

  • Better tolerated

  • It is used in rheumatoid arthritis, acute gout

  • 9.

    Flurbiprofen

Oral
Topical (eye drops)
  • It is used in osteoarthritis, rheumatoid arthritis and ocular inflammation

Selective COX-2 inhibitors

Some of the COX-2 inhibitors are parecoxib, etoricoxib, etc.

Parecoxib is a p rodrug of valdecoxib and is administered p arenterally; celecoxib and e toricoxib are given by e nteral route ( Table 6.6 ).

Table 6.6 ■
Differences between nonselective COX and selective COX-2 inhibitors
Nonselective COX inhibitors Selective COX-2 inhibitors
  • Analgesic effect +

  • Antipyretic effect +

  • Anti-inflammatory effect +

  • Antiplatelet effect +

  • GI side effects are marked ++

  • Renal toxicity + (sodium and water retention)

  • Analgesic effect +

  • Antipyretic effect +

  • Anti-inflammatory effect +

  • No antiplatelet effect

  • GI side effects are less (less ulcerogenic potential)

  • Renal toxicity +

Note: +, present; ++, effect is more.

Paracetamol (acetaminophen)

Paracetamol is effective by oral and parenteral routes. It is well absorbed, widely distributed all over the body, metabolized in liver by sulphate and glucuronide conjugation. The metabolites are excreted in urine ( Table 6.7 ).

Table 6.7 ■
Differences between aspirin and paracetamol
Aspirin Paracetamol (acetaminophen)
  • 1.

    It is a salicylate derivative

  • 2.

    It has analgesic, antipyretic and potent anti-inflammatory effects

  • 3.

    It causes GI irritation (nausea, vomiting, peptic ulcer and bleeding)

  • 4.

    In large doses, it produces acid–base and electrolyte imbalances

  • 5.

    It has antiplatelet action

  • 6.

    It has no specific antidote

  • 7.

    It is contraindicated in peptic ulcer, people with bleeding tendency, bronchial asthma and in children with viral infection

  • 1.

    It is a para -aminophenol derivative

  • 2.

    It has potent antipyretic and analgesic effects with poor anti-inflammatory activity

  • 3.

    It usually does not produce gastric irritation

  • 4.

    It does not produce acid–base and electrolyte imbalances

  • 5.

    It has no antiplatelet action

  • 6.

    N -acetylcysteine is the antidote

  • 7.

    Paracetamol is the preferred analgesic and antipyretic in patients with peptic ulcer, bronchial asthma and in children

Uses

  • 1.

    As antipyretic: To reduce body temperature during fever.

  • 2.

    As analgesic: To relieve headache, toothache, myalgia, dysmenorrhoea, etc.

  • 3.

    It is the preferred analgesic and antipyretic in patients with peptic ulcer, haemophilia, bronchial asthma and children.

Adverse effects

  • 1.

    Side effects are rare, occasionally causes skin rashes and nausea.

  • 2.

    Hepatotoxicity: With acute overdose or chronic use.

  • 3.

    Nephrotoxicity is commonly seen on chronic use.

Acute paracetamol poisoning.

Acute overdosage mainly causes hepatotoxicity – the symptoms are nausea, vomiting, diarrhoea, abdominal pain, hypoglycaemia, hypotension, hypoprothrombinaemia, coma, etc. Death is usually due to hepatic necrosis.

Mechanism of toxicity and its treatment ( fig. 6.5 )

  • The toxic metabolite of paracetamol is detoxified by conjugation with glutathione and gets eliminated.

  • High doses of paracetamol cause depletion of glutathione levels. In the absence of glutathione, toxic metabolite (N-acetyl-p-benzo-quinoneimine [NAPQI]) binds covalently with proteins in the liver and kidney and causes necrosis.

  • Alcoholics and premature infants are more prone to hepatotoxicity.

  • N-acetylcysteine or oral methionine replenishes the glutathione stores of the liver and protects liver cells.

  • Activated charcoal is administered to decrease the absorption of paracetamol from the gut.

  • Haemodialysis may be required in cases with acute renal failure.

Fig. 6.5
Mechanism of paracetamol toxicity and its treatment. NAPQI, N-acetyl-p-benzo-quinoneimine.

Topical NSAIDs

Topical formulations of NSAIDs are available. Systemic toxicity is minimal. Diclofenac, ibuprofen, naproxen, etc. are useful topically for musculoskeletal pain. They are used in backache, osteoarthritis, sprain, etc. Flurbiprofen and diclofenac eye drops are used in ophthalmic practice.

Drugs used in the treatment of gout PH1.16

Gout is a disorder of purine metabolism in which plasma urate concentration is raised either due to overproduction or impaired excretion of uric acid. It is characterized by intermittent attacks of acute arthritis produced by deposition of sodium urate crystals in joints.

Primary hyperuricaemia may be idiopathic or due to enzyme defects. Secondary hyperuricaemia can occur in leukaemias, chronic renal failure and during drug therapy (thiazides, loop diuretics, pyrazinamide, levodopa, cytotoxic agents, etc.).

Classification

  • 1.

    Acute gout

    • (a)

      NSAIDs: Indomethacin, naproxen, diclofenac, aceclofenac, piroxicam, sulindac, etoricoxib

    • (b)

      Colchicine

    • (c)

      Glucocorticoids: Prednisolone, methylprednisolone, triamcinolone

  • 2.

    Long-term control of gout or hyperuricaemia

    • (a)

      Uricosuric agents: Probenecid, sulphinpyrazone

    • (b)

      Uric acid synthesis inhibitors: Allopurinol, febuxostat

Treatment of acute attack of gout

Nonsteroidal anti-inflammatory drugs

To relieve an acute attack, NSAIDs like naproxen, indomethacin, piroxicam, diclofenac, aceclofenac and etoricoxib are used. They are better tolerated than colchicine.

Colchicine.

It is an alkaloid. It is neither an analgesic nor a uricosuric agent, although it relieves pain in acute attack of gout. Deposition of urate crystals in the joint → chemotactic factors produced → migration of neutrophils into the joint → release factors which contribute to inflammation. Colchicine prevents release of chemotactic factors and inhibits migration of neutrophils to the affected area. It is administered either orally or intravenously. It is rapid acting but poorly tolerated. They are nausea, vomiting, diarrhoea and abdominal pain. Chronic use may lead to myopathy, alopecia, aplastic anaemia and agranulocytosis.

Glucocorticoids.

Glucocorticoids are effective, produce rapid response and are reserved for cases not responding to NSAIDs and colchicine. Prednisolone and methylprednisolone are used systemically in gout. If a single joint is affected, then intra-articular triamcinolone is effective.

Treatment of chronic gout

Uricosuric agents

They inhibit active tubular reabsorption of uric acid in proximal tubules and increase excretion of uric acid, e.g. probenecid and sulphinpyrazone. They are rapid acting but poorly tolerated. High fluid intake is advised to prevent formation of urate crystals in urine. Sulphinpyrazone is an alternative to probenecid. Uricosuric drugs should not be given within 3 weeks of an acute attack of gout. They mobilize uric acid from tophaceous deposits, hence there is fluctuation in serum uric acid levels which can precipitate an acute attack. These drugs are contraindicated in patients with renal failure. Side effects are rare, but GI toxicity (nausea, vomiting) and skin rashes may occur.

Drug interactions

Probenecid × β-lactam antibiotics (penicillins, cephalosporins)

They are excreted by active tubular secretion. When they are administered simultaneously, probenecid competes with penicillins/cephalosporins and blocks the tubular secretion of β-lactam antibiotics. Therefore, plasma levels of β-lactam antibiotics and their duration of action increases. Thus, the treatment becomes more effective.

Uric acid synthesis inhibitors

Allopurinol.

Allopurinol prevents the synthesis of uric acid by inhibiting the enzyme xanthine oxidase, thus reduces the plasma urate levels. Its active metabolite, alloxanthine, is a noncompetitive inhibitor of xanthine oxidase enzyme. It reduces urate crystals in the kidney, joints and soft tissue. There is an increase in the levels of xanthine and hypoxanthine in plasma which are effectively excreted in urine.

Allopurinol is administered orally and is the drug of choice for asymptomatic gout. It is used in chronic gout as well as hyperuricaemia associated with cancer chemotherapy, radiation or renal disease. It should not be started within 3 weeks of an acute attack of gout, as it may precipitate another attack. Allopurinol is also useful in kala-azar.

Adverse effects

  • 1.

    Hypersensitivity: Skin rashes, itching, erythema, headache, fever and rarely Stevens–Johnson syndrome may occur.

  • 2.

    GIT: Nausea, vomiting, diarrhoea and occasionally hepatotoxicity may also occur.

Allopurinol is contraindicated in children, pregnancy, lactation, patients with liver and kidney diseases.

Drug interactions

Allopurinol × 6-mercaptopurine

Allopurinol interferes with the metabolism of 6-mercaptopurine by inhibiting the enzyme xanthine oxidase and increases its effect. Therefore, allopurinol is commonly used in cancer patients receiving chemotherapy to reduce hyperuricaemia, decrease the dose of 6-mercaptopurine and its side effects.

Febuxostat.

It is a xanthine oxidase inhibitor → decreases formation of uric acid. It is administered orally (once daily dose is used) for chronic gout. Adverse effects include diarrhoea, headache and hepatotoxicity. Febuxostat can be used in gout in patients intolerant to allopurinol.

Rasburicase.

It is a urate oxidase produced by recombinant technology. It converts uric acid to soluble allantoin.

It is infused to decrease serum uric acid levels in children with leukaemia on anticancer drug therapy. Haemolysis, gastrointestinal disturbances, hypersensitivity reactions may occur.

Pegloticase.

It converts uric acid to allantoin which is soluble and easily excreted in urine. It is administered as i.v. infusion in cases not responding to other drugs. Anaphylaxis can occur.

Drugs used in the treatment of rheumatoid arthritis PH1.16

Rheumatoid arthritis (RA) is a chronic multisystem autoimmune disease of unknown cause. Although there are a variety of systemic manifestations, the main characteristic feature is persistent inflammatory synovitis of peripheral smaller joints. The course of the disease is prolonged with exacerbation and remissions. Pain and swelling of the joints are mainly due to PGs, whereas cytokines are responsible for progressive damage to the joints leading to deformity.

Drugs used in the treatment of RA:

  • 1.

    Disease-modifying antirheumatic drugs (DMARDs)

    • (i)

      Nonbiologics

      • Methotrexate, azathioprine, cyclophosphamide, cyclosporine, chloroquine, hydroxychloroquine, sulphasalazine, leflunomide, gold salts, d-penicillamine.

    • (ii)

      Biologics

      • (a)

        TNF-α antagonists: Etanercept, infliximab, adalimumab

      • (b)

        IL-1 antagonist: Anakinra

      • (c)

        T-cell modulating agent: Abatacept

      • (d)

        B-lymphocyte depleter: Rituximab

  • 2.

    NSAIDs: Aspirin, ibuprofen, diclofenac, naproxen, piroxicam, etoricoxib.

  • 3.

    Glucocorticoids: Prednisolone, triamcinolone, methylprednisolone.

  • M – Methotrexate

  • E – Etanercept

  • D – D-Penicillamine

  • I – Infliximab

  • C – Chloroquine and hydroxychloroquine

  • A – Anakinra, abatacept

  • L – Leflunomide

  • S – Sulphasalazine

  • R – Rituximab

    • Gold compounds

Note: Mnemonic for DMARDs – M E D I C A L S R Gold ( E, I, A and R are biologics).

Nonsteroidal anti-inflammatory drugs

Rapidly produce symptomatic relief – they reduce inflammation, pain, stiffness and swelling but they have little effect on the progression of bone and cartilage destruction.

Disease-modifying antirheumatic drugs

Nonbiologics

They relieve symptoms as well as reduce disease activity in RA. The effects of DMARDs may take few weeks to several months to become evident. Once a diagnosis of RA is made, the patient should be started on a DMARD.

Methotrexate

It is the preferred DMARD in the treatment of RA. It has relatively more rapid onset of action than other DMARDs. It is a folate antagonist. The dose of methotrexate used in RA is much lower than the dose needed in cancer chemotherapy. It exerts anti-inflammatory effect. It inhibits chemotaxis of neutrophils and decreases production of proinflammatory cytokines by activated T cells. Methotrexate is administered orally starting with a dose of 7.5–15 mg once weekly and increasing the dose by 2.5 mg weekly if there is no improvement. It can also be used in psoriasis, polymyositis, giant cell arteritis, dermatomyositis, etc.

Adverse effects.

They include nausea, vomiting, mucosal ulcers and dose-dependant hepatotoxicity. Hence, hepatic function should be monitored periodically. The adverse effects can be minimized by administration of folic acid or folinic acid. Methotrexate is contraindicated in pregnancy, liver disease and peptic ulcer.

Chloroquine and hydroxychloroquine

These are antimalarial drugs – also useful in RA. The exact mechanism of action of these drugs in RA is not clear. They decrease release of lysosomal enzymes and scavenge free radicals. They are well tolerated. They are administered orally, highly bound to tissue proteins and deposited in melanin containing tissues, especially eye. Prolonged administration may cause corneal opacity and retinal damage. Hence, ophthalmologic examination should be done at least once a year in patients on chloroquine/hydroxychloroquine. The other side effects are nausea, vomiting and skin rashes. The drug is relatively safe in pregnancy. They are used alone in patients with mild disease or in combination with methotrexate and/or sulphasalazine.

Sulphasalazine

It is used alone in mild disease or in combination with other drugs in severe cases. It causes remission in active RA and is also used for chronic inflammatory bowel disease. It is administered orally and is split in the gut by colonic bacteria. Common side effects are nausea, vomiting, diarrhoea, headache, skin rashes and leukopaenia.

Leflunomide

Its active metabolite inhibits dihydroorotate dehydrogenase, thus decreases pyrimidine synthesis. It inhibits T-cell proliferation. L eflunomide is used alone or in combination with methotrexate for the treatment of RA. It is as effective as methotrexate. It is completely absorbed after oral administration and has a l ong plasma half-life of about 2–3 weeks. Hence, a l oading dose is given. Adverse effects include l oose stools (diarrhoea), l oss of hair, l iver toxicity (hepatotoxicity), l eukopaenia and skin rashes. It is contraindicated in children, in pregnant women and l actating mothers. ( Note ‘L’s. )

Gold compounds

They are not used because of their toxicity.

D-penicillamine

It is a metabolite of penicillin and rarely used now because of toxicity.

Adverse effects are proteinuria, pruritus, pancytopaenia, pemphigus-like skin rashes, thrombocytopaenia and GI side effects.

Biologics

Biologics are preparations made from microorganisms, animals or human or their products. They are administered parenterally. These agents are used in case of RA not responding to nonbiological agents. They are also useful in other autoimmune disorders like psoriasis, Crohn disease, ankylosing spondylitis and scleroderma ( Table 6.8 ).

Table 6.8 ■
Biologics and their important features
Drug Route MOA Adverse effects Uses
  • Etanercept

  • Infliximab

  • Adalimumab

  • Golimumab

s.c. TNF-α antagonists Opportunistic infections including tuberculosis Rheumatoid arthritis, psoriasis, Crohn disease, ankylosing spondylitis
Anakinra s.c. IL-1 antagonist Opportunistic infections, mainly respiratory Rheumatoid arthritis
Abatacept i.v. infusion Inhibits T-cell activation Opportunistic infections Rheumatoid arthritis
Rituximab i.v. infusion Depletes peripheral B lymphocytes Skin rashes Used with methotrexate in resistant cases of rheumatoid arthritis
Note: MOA, mechanism of action.

Prolonged use may produce opportunistic infections like tuberculosis, P. jiroveci infection and urinary tract infection.

Glucocorticoids

These are adjuvant drugs in RA. Their effects are prompt and they suppress inflammation quickly. They are administered either systemically or topically (intra-articular). Glucocorticoids are also used for certain serious extra-articular manifestations or during periods of exacerbation. Prolonged use of glucocorticoids leads to adverse effects.

Respiratory system PH1.33

Drugs used in the treatment of cough

Cough is a protective reflex, intended to remove irritants and accumulated secretions from the respiratory passages. The drugs used in the symptomatic treatment of cough are as follows:

  • 1.

    Antitussives: Codeine, pholcodine, noscapine, dextromethorphan, prenoxdiazine, chlophedianol and antihistamines.

  • 2.

    Pharyngeal demulcents: Lozenges, syrups, liquorice.

  • 3.

    Expectorants: Sodium and potassium citrate, potassium iodide, guaiphenesin, ammonium chloride.

  • 4.

    Mucolytics: Bromhexine, acetylcysteine, carbocisteine, ambroxol.

Cough may be:

  • 1.

    Productive cough: Helps to clear the airway. Suppression of productive cough is harmful as it may lead to infections. Treatment includes antibiotics for infection, expectorants and mucolytics for cough.

  • 2.

    Nonproductive cough: It should be suppressed.

Antitussives

They inhibit cough reflex by suppressing the cough centre in medulla. They are used for symptomatic treatment of dry, unproductive cough. Antitussives should be avoided in children younger than 1 year.

  • 1.

    Codeine:

    • (a)

      Has cough centre suppressant effect.

    • (b)

      Causes mild CNS depression, hence drowsiness can occur.

    • (c)

      Causes constipation by decreasing intestinal movements.

    • (d)

      Should be avoided in children and asthmatics.

      • Codeine is administered orally, has mild analgesic effect and less addiction liability than morphine.

  • 2.

    Pholcodine: Antitussive action is similar to codeine. It has no analgesic or addiction liability. It is administered orally and has a long duration of action.

  • 3.

    Noscapine: It is an opium alkaloid and has potent antitussive effect. It is useful in spasmodic cough. It has no analgesic effect, does not cause constipation, addiction or CNS depression. The side effects are nausea and headache; bronchospasm can occur in asthmatics.

  • 4.

    Dextromethorphan: It is a centrally acting antitussive agent. It has no analgesic property, does not cause constipation and addiction; mucociliary function in respiratory passages is not affected. It may cause sedation and hallucinations.

  • 5.

    Antihistamines: Diphenhydramine, chlorpheniramine, promethazine, etc. are useful in cough due to their sedative, antiallergic and anticholinergic actions. They produce symptomatic relief in cold and cough associated with allergic conditions of respiratory tract.

  • 6.

    Prenoxdiazine: It acts peripherally on stretch receptors on the airways.

Pharyngeal demulcents

Syrups, lozenges, linctuses or liquorice may be used when cough arises due to irritation above the larynx. They increase salivation and produce protective soothing effect on the inflamed mucosa.

Syrup is a concentrated solution of sugar containing the drug to mask the bitter taste of the drug.

Lozenge, solid dosage form placed in the mouth and sucked; it dissolves slowly to liberate the active ingredient. It soothes the irritated mucosa of the throat, e.g. dyclonine (local anaesthetic) lozenge for sore throat.

Linctus, viscous liquid sipped slowly to allow it trickle down the throat; used for relief of cough, e.g. linctus codeine.

Expectorants (mucokinetics)

They increase the volume of bronchial secretion and decrease viscosity of the sputum; hence, cough becomes less tiring and productive. They include iodides, chlorides, bicarbonates, acetates, volatile oils, etc.

Mucolytics

These agents break the thick tenacious sputum and lower the viscosity of sputum, so that sputum comes out easily with less effort.

Bromhexine.

It is a semisynthetic agent used orally. It has potent mucolytic and mucokinetic effects.

Bromhexine liberates→ lysosomal enzymes → digest the mucopolysaccharides → decreases viscosity of sputum → cough becomes less tiring and productive.

The side effects are rhinorrhoea and lacrimation.

Acetylcysteine and carbocisteine.

Acetylcysteine is a mucolytic used as an aerosol in the treatment of cough.

Acetylcysteine and carbocisteine → open disulphide bonds in mucoproteins of sputum → sputum becomes thin and less viscid → cough becomes less tiring and productive.

The side effects are nausea, vomiting and bronchospasm.

Carbocisteine is administered orally. It may cause gastric irritation, hence should be avoided in patients with peptic ulcer.

Drugs used in the treatment of bronchial asthma PH1.32

In bronchial asthma, there is impairment of airflow due to contraction of bronchial smooth muscle (bronchospasm), swelling of bronchial mucosa (mucosal oedema) and increased bronchial mucus secretion. There is inflammation and hyperresponsiveness of airways.

Several factors may precipitate attacks of asthma in susceptible individuals. They include allergy, infection and psychological factors. The airway obstruction in asthma is mainly due to the release of mediators from sensitized mast cells in the lungs. They are histamine, 5-HT (serotonin), PGs, leukotrienes (LTC 4 and LTD 4 ), proteases, PAF, etc. Bronchial asthma may be either episodic or chronic.

Acute asthma.

It is characterized by episodes of dyspnoea associated with expiratory wheezing.

Chronic asthma.

There is continuous wheeze and breathlessness on exertion; cough and mucoid sputum with recurrent respiratory infection are common.

Status asthmaticus (acute severe asthma).

When an attack of asthma is prolonged with severe intractable wheezing, it is known as acute severe asthma.

Classification of antiasthmatic drugs

  • 1.

    Bronchodilators

    • (a)

      Sympathomimetics

      • Selective β 2 -adrenergic agonists: Salbutamol and terbutaline (short acting); bambuterol, salmeterol and formoterol (long acting).

    • (b)

      Methylxanthines: Theophylline, aminophylline, etophylline, doxophylline.

    • (c)

      Anticholinergics: Ipratropium bromide, tiotropium bromide.

  • 2.

    Leukotriene receptor antagonists: Zafirlukast, montelukast, zileuton.

  • 3.

    Mast cell stabilizers: Sodium cromoglycate, ketotifen.

  • 4.

    Glucocorticoids

    • (a)

      Inhaled glucocorticoids: Beclomethasone, budesonide, fluticasone, ciclesonide.

    • (b)

      Systemic glucocorticoids: Hydrocortisone, prednisolone, methylprednisolone.

  • 5.

    Anti-IgE monoclonal antibody: Omalizumab.

Sympathomimetics

Mechanism of action

Adrenaline (nonselective sympathomimetic).

It produces prompt and powerful bronchodilatation by acting through β 2 -adrenergic receptors. It is useful in acute attack of asthma (not responding to other drugs) – 0.2–0.5 mL of 1:1000 solution given subcutaneously. Its use has declined because of its dangerous cardiac side effects.

Selective β 2 -adrenergic agonists ( table 6.9 ).

They are the first-line drugs for bronchial asthma. For mechanism of action – see flowchart given above.

Table 6.9 ■
Selective β 2 -agonists
Salbutamol and terbutaline Salmeterol Formoterol
Selective β 2 -agonists: On inhalation, they have a rapid onset (within 1–5 minutes) and short duration of action; they are preferred for acute attack of asthma
Route and dose : Inhalation, salbutamol 100–200 mcg every 6 hours, or as and when required through metered-dose inhaler (MDI) to terminate an acute attack; other routes of administration are oral, i.m. and i.v.
Long-acting selective β 2 -agonist: It is preferred for moderate to severe, persistent asthma; it is not suitable for acute attack as it has a slow onset of action
Route and dose : Inhalation, 50 mcg twice daily
Long-acting selective β 2 - agonist: It has a rapid onset of action; it is preferred for moderate to severe persistent asthma due to its long duration of action
Route and dose : Inhalation, 12–24 mcg twice daily

They are well tolerated when inhaled. They may cause tremor, tachycardia, palpitation, hypokalaemia and rarely cardiac arrhythmias.

Bambuterol

  • Prodrug of terbutaline

  • Is administered orally – once daily dose is used

  • Has long duration of action

Methylxanthines.

Use of methylxanthines in asthma has markedly diminished because of their narrow margin of safety and availability of better antiasthmatic drugs (selective β 2 -agonists, inhaled steroids and leukotriene antagonists).

Mechanism of action of methylxanthines

Methylxanthines inhibit phosphodiesterases (PDEs), thereby prevent degradation of cAMP and cGMP. This results in accumulation of intracellular cAMP and in some tissues, cGMP. Methylxanthines are competitive antagonists at adenosine receptors, which also results in bronchodilatation.

Pharmacokinetics.

Methylxanthines are well absorbed after oral and parenteral administration; food delays the rate of absorption of theophylline. They are well distributed all over the body; they cross placental and blood–brain barrier. They get metabolized in liver and excreted in urine.

  • 1.

    Theophylline: It is poorly water soluble, hence not suitable for injection. It is available for oral administration.

  • 2.

    Aminophylline: It is water soluble but highly irritant. It can be administered orally or slow intravenously.

  • 3.

    Etophylline: It is water soluble and can be given by oral, i.m. or i.v. routes.

  • 4.

    Doxophylline

    • Methylxanthine derivative

    • Orally administered – once or twice daily dose is used

    • Less likely to cause GI and CNS side effects

Adverse effects.

They have a narrow margin of safety. They can cause tachycardia, palpitation, hypotension and sometimes sudden death due to cardiac arrhythmias ( Fig. 6.6 ).

Fig. 6.6
Adverse effects of methylxanthines.

Drug interactions

  • 1.

    Sympathomimetics × methylxanthines

    • Methylxanthines potentiate the effects of sympathomimetics:

      • (a)

        Bronchodilatation (beneficial effect)

      • (b)

        Cardiac stimulation (harmful effect)

  • 2.

    Phenytoin/rifampicin/phenobarbitone × theophylline: They are enzyme inducers; hence, they accelerate the metabolism of theophylline and decrease its effect.

  • 3.

    Cimetidine/ciprofloxacin/erythromycin × theophylline: They are enzyme inhibitors; hence, potentiate the effects of theophylline by interfering with its metabolism.

Uses of methylxanthines

  • 1.

    Bronchial asthma and COPD: Theophylline is used as an additional drug in moderate or severe persistent bronchial asthma.

  • 2.

    Apnoea in premature infants: Aminophylline/caffeine is used intravenously to reduce the duration of apnoea episodes. Caffeine is safer than aminophylline.

Anticholinergics.

Ipratropium bromide and tiotropium bromide are atropine substitutes. They selectively block the effects of acetylcholine in the bronchial smooth muscle and cause bronchodilatation. They do not affect mucociliary clearance. They have a slow onset of action and are less effective than sympathomimetic drugs in bronchial asthma. These anticholinergics are the preferred bronchodilators in COPD and can also be used in bronchial asthma. They are administered by inhalational route, and act primarily on larger airways. Tiotropium is longer acting and more efficacious than ipratropium.

Combined use of ipratropium with β 2 -adrenergic agonists produces greater and more prolonged bronchodilatation, hence used in acute severe asthma.

Leukotriene-receptor antagonists

These drugs competitively block the effects of cysteinyl leukotrienes (LTC 4 and LTD 4 ) on bronchial smooth muscle.

Thus, they produce bronchodilatation, suppress bronchial inflammation and decrease hyperreactivity. They are well absorbed after oral administration, highly bound to plasma proteins and metabolized extensively in the liver. They are effective for prophylactic treatment of mild asthma and moderate persistent asthma (in combination with other drugs). They are well tolerated, produce few adverse effects – headache, skin rashes and rarely eosinophilia.

Zileuton

  • Inhibits 5-lipoxygenase and is administered orally

  • Hepatotoxicity restricts its use

Mast cell stabilizers

Sodium cromoglycate (cromolyn sodium) and ketotifen are mast cell stabilizers. They are not bronchodilators. They inhibit the release of various mediators – histamine, LTs, PGs, PAF, etc. by stabilizing mast cell membrane ( Fig. 6.7 ). They also reduce bronchial hyperreactivity to some extent but the AG:AB reaction is not affected. Onset of action is slow.

Fig. 6.7
Mechanism of action of mast cell stabilizers.

Sodium cromoglycate is not effective orally as it is poorly absorbed from the gut. In bronchial asthma, sodium cromoglycate is given by inhalation.

Uses

  • 1.

    Allergic asthma: As a prophylactic agent to prevent bronchospasm induced by allergens and irritants.

  • 2.

    It can also be used in allergic conjunctivitis, allergic rhinitis, allergic dermatitis, etc. by topical route as a prophylactic agent.

Adverse effects.

Systemic side effects are rare; it may cause symptoms of local irritation – cough, bronchospasm, headache, nasal congestion, etc.

Ketotifen.

Mechanism of action is similar to sodium cromoglycate, has additional H 1 -blocking effect. It is orally effective but has a slow onset of action.

Glucocorticoids

  • 1.

    Systemic: Hydrocortisone, prednisolone, methylprednisolone and others.

  • 2.

    Inhalational: Beclomethasone, budesonide, fluticasone and ciclesonide.

Glucocorticoids induce synthesis of ‘lipocortin’, which inhibits phospholipase A 2 and thereby prevent the formation of various mediators such as PGs, TXA 2 and SRS-A. Glucocorticoids have antiallergic, anti-inflammatory and immunosuppressant effects. They:

  • 1.

    Suppress inflammatory response to AG:AB reaction.

  • 2.

    Decrease mucosal oedema.

  • 3.

    Reduce bronchial hyperreactivity.

Glucocorticoids do not have direct bronchodilating effect but they potentiate the effects of β 2 -adrenergic agonists. They also prevent development of tolerance to β 2 -adrenergic agonists.

Inhaled glucocorticoids such as beclomethasone, budesonide, fluticasone and ciclesonide are used as prophylactic agents in bronchial asthma. Inhaled glucocorticoids are used in patients with persistent asthma who require inhaled β 2 -agonists frequently. Ciclesonide is a prodrug, gets activated by esterases in bronchial epithelium. They are well tolerated. Systemic side effects are minimal with these agents. The common side effects are hoarseness of voice, dysphonia and oropharyngeal candidiasis. These can be reduced by using a spacer, rinsing the mouth after each dose; oral thrush can be treated effectively by topical antifungal agent, nystatin or hamycin.

Combination of long-acting beta-agonist (LABA) with steroid is available, e.g. fluticasone + salmeterol; budesonide + formoterol. They have synergistic action; used in bronchial asthma and COPD. They are used in moderate and severe persistent asthma.

Systemic glucocorticoids are used in acute severe asthma and chronic severe asthma. Long-term use of systemic steroids produce severe side effects such as gastric irritation, Na + and water retention, hypertension, muscle weakness, osteoporosis and HPA axis suppression.

Anti-IgE monoclonal antibody: Omalizumab

Omalizumab prevents the binding of IgE to mast cell, thus prevents mast cell degranulation. It has no effect on IgE already bound to mast cells. It is administered parenterally. It is used in moderate to severe asthma and allergic disorders such as nasal allergy and food allergy. It is approved for use in patients older than 12 years. It causes local side effects such as redness, stinging, itching and induration.

Inhalational devices.

They are

  • Pressurized metered-dose inhaler (pMDI) – It is a handheld device which can be used alone or with spacer. It has a pressurized container (canister) with drug along with a propellant (hydrofluroalkane, HFA) and other substances as solution or suspension. A specific amount of drug is delivered as a fine aerosol into the airways. The small particles reach the smaller airways whereas large ones are deposited in the oral cavity (minimized by using spacer). Proper coordination is required between use of device and breathing (difficult for children and elderly). Patient has to be trained on correct use of device.

  • Dry powder inhalers – Spinhaler and Rotahaler. A capsule (rotacap) containing the drug in fine powder form is placed in the Rotahaler.

  • Nebulizers – useful in acute severe asthma, COPD and for delivering drug in young children and elderly. The drug is delivered in the form of a mist which can easily reach the airways. They are expensive but do not require coordination unlike pMDI.

Antiasthmatic agents available for inhalation are β 2 -adrenergic agonists (salbutamol, terbutaline, salmeterol and formoterol), anticholinergics (ipratropium bromide and tiotropium bromide), mast cell stabilizers (sodium cromoglycate) and glucocorticoids (fluticasone, beclomethasone, budesonide, etc.).

Treatment of acute severe asthma (status asthmaticus)

  • 1.

    Humidified oxygen inhalation.

  • 2.

    Nebulized β 2 -adrenergic agonist (salbutamol 5 mg/terbutaline 10 mg) + anticholinergic agent (ipratropium bromide 0.5 mg).

  • 3.

    Systemic glucocorticoids: Intravenous hydrocortisone 200 mg i.v. stat followed by i.v. hydrocortisone 100 mg q6h or oral prednisolone 30–60 mg/day depending on the patient’s condition.

  • 4.

    Inj salbutamol 0.4 mg i.m.

  • 5.

    Intravenous fluids to correct dehydration.

  • 6.

    Potassium supplements: To correct hypokalaemia produced by repeated doses of salbutamol/terbutaline.

  • 7.

    Sodium bicarbonate to treat acidosis.

  • 8.

    Antibiotics to treat infection.

Drugs to be avoided in patients with bronchial asthma

  • 1.

    NSAIDs like aspirin, ibuprofen and diclofenac (paracetamol can be used).

  • 2.

    β-Adrenergic blockers.

  • 3.

    Cholinergic agents.